The research project is aimed at the description and characterization of the physical states of the sodium and potassium channels in excitable cells. Experiments are proposed for studying 1) the electrical manifestations of the molecular rearrangements responsible for channel gating (gating currents), 2) the macroscopic conductance changes associated to channel opening and closing, and 3) the fluctuations of the channel conductance expressed as noise or single channel events. Results of these experiments will be analyzed and interpreted with the help of a model, proposed here, that will also be used (and modified) to correlate the observations on gating currents, ionic currents and fluctuation experiments. Several drugs and membrane modifiers will be tested to complete the description of the states of the channels. Experiments will be performed in squid giant axons under voltage clamp using the standard perfusion techniques and the new cut-open axon preparation. We propose to extend this latter technique to allow patch recording of noise and single channels. Our studies are expected to provide new information on how the membrane voltage controls channel function at the physico-chemical level and will help in the understanding of the structural modifications of the channel during its normal operation. These studies are expected to be of importance in the physiology of nerve, muscle and other excitable tissues.